Protein tyrosine phosphatases (PTPs) represent a highly diverse family of enzymes that have a pivotal role in cell proliferation, differentiation, and transformation. Fischer, E. H., Charbonneau, H., and Tonks, N. K. (1991) Science 253:401-6; Walton, K. M. and Dixon, J. E. (1993) Annu. Rev. Biochem. 62:101-20; Hunter, T. (1995) Cell 80:225-236. SHP-1 and SHP-2, representing a subfamily of PTPs containing SH2 domains have been extensively studied in recent years. Zhao, Z, Shen, S. H. and Fischer, E. H. (1995) Adv. in Protein Phosphatases 9:297-317; Streuli, M. (1996) Curr. Opinion in Cell Biol. 183: 182-188; Scharenberg, A. M. and Kinet, J. P. (1996) Cell 87:961-964; Tonks, N. K., & Neel, B. G. (1996) Cell 87:365-368; Frearson, J. A. and Alexander, D. R. (1997) Bioessays 19;417-427; Ulyanova, T., Blasioli, J., and Thomas, M. L. (1997) Immunolog. Res. 16:101-113; Byon, J. C., et al. (1997) Proc. Soc. Exp. Biol. & Med. 216:1-20; Neel, B. G. and Tonks, N. K. (1997) Curr. Opin. Cell. Biol. 9:193-204.
SHP-1 and SHP-2 share nearly 60% overall sequence identity and are regulated in similar manners. Nevertheless, in many systems, they have distinct physiological functions. SHP-1 has a negative role in proliferation of hematopoietic cells whereas SHP-2 is a positive transducer of growth factor signal transduction. This distinction in functions is presumably due to different physiological targets.
Recently, a number of putative substrates of SHP-1 and SHP-2 have been identified. Xiao, S., et al. (1994) J. Biol. Chem. 269:21244-21248; Milarski, K. L. and Saltiel, A. L. (1994) J. Biol. Chem. 269:21239-21243; Noguchi, T., et al. (1994) Mol. Cell. Biol. 14:6674-6682; Yamauchi, K., et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92:664-668; Yamauchi, K., et al. (1995) J. Biol. Chem. 270:17716-17722; Frearson, J. A., Yi, T., and Alexander, D. R. (1996) Eur. J. Immunol. 26:1539-1543; Valiante, N. M., et al. (1996) J. Exp. Med. 184:2243-2250; Carlberg, K. and Rohrschneider, L. R. (1997) J. Biol. Chem. 272:15943-15950; Ruff, S. J., Chen, K., and Cohen S. (1997) J. Biol. Chem. 272:1263-1267; Gu, H., Griffin, J. D., and Neel, B. G. (1997) J. Biol. Chem. 272:16421-16430; Jiao, H., et al. (1997) Exp. Hematol. 25:592-600. One of them, designated as SIRP or SHPS-1, has been cloned (Kharitonenkov, A., et al. (1997) Nature 386:181-186; Fujioka, Y., et al. (1996) Mol. Cell. Biol. 16:6887-6899). Overexpression of catalytically inactive mutants of SHP-1 and SHP-2 resulted in the identification of several hyper-phosphorylated proteins associated with the inactive SHP-1 and/or SHP-2 (Zhao, Z., et al. (1995) J. Biol. Chem. 270:11765-17769; Su, L., et al. (1996) J. Biol. Chem. 271:10385-10390.
Although a number of putative substrates of SHP-2 have been identified, little is known at the molecular level about the signaling mechanisms of SHP-2. This lack of knowledge represents a serious deficiency in the art in view of the effects of SHP-2 as described above. Therefore, further characterization of SHP-2 signaling in vertebrates, particularly in mammals, and more particularly in humans is needed. A novel isolated and purified polypeptide having a role in SHP-2 signaling would have broad utility in view of the above-described various and multiple physiological roles of SHP-2.